In order for vascularly infused stem cells to reach targeted organ for repair or circulating tumor cells to leave the primary site for metastasis, the first step is that the cells need to transmigrate across the blood vessel wall. Although such transmigration does occur, the exact mechanism is elusive. It has been postulated that the injected stem cells or circulating tumor cells undergo a process similar to leukocytes or white blood cells, termed diapedesis. In this process, white blood cells in the lumen squeeze through the endothelial barrier of the blood vessel into the surrounding tissue. However, our lab has discovered injected cells undergo an extravasation process distinct significantly from diapedesis. We have named this new extravasation process Angiopellosis (?angio?: relating to blood vessels; ?pello?: push, drive out). During the angiopellosis process, the vascular wall undergoes extensive remodeling to allow the cell to exit the lumen, while the cell itself remains distinctively passive in activity. Angiopellosis supports the group extravasation phenomenon that does not fit the conventional diapedesis theory. Our central hypothesis is that alterations in cell clustering and molecular pathways involved in angiopellosis can significantly change the efficiency of cell extravasation, impacting the safety and efficacy of stem cell transplantation and increasing understanding of cancer cell metastasis. Our preliminary data suggests adhesion molecules such as integrins and secreted proteins such as matrix metalloproteinases are critical to angiopellosis. In this grant study, we plan to employ in vitro blood vessel models and in vivo zebrafish and mouse models of vasculatures to study angiopellosis, with state-of-art imaging techniques and series of gain- and loss-of-function experiments. AIM 1 is to decipher the molecular control of the angiopellosis process in injected stem cells and cancer cells. AIM 2 is to test the ability of angiopellosis agonists to improve infused stem cell engraftment/efficacy. AIM 3 is to examine the potential of angiopellosis-enabling microparticles for extravasation and regeneration in heart injury. Our study will provide new insights on cell extravasation and complement the current solitary diapedesis theory. Together, the proposed mechanistic and translational experiments will provide a scientific premise to understand cell extravasation while suggesting targets for therapeutic intervention and promoting stem cell transplantation technologies.